Substituted beta-arylamidoacrylic acids

ABSTRACT

Certain substituted Beta -arylamidoacrylic acids and a method of preparing them are disclosed. These compounds are useful as antiinflammatory and diuretic agents.

United States Patent [191 Buckler et a1.

[ 1 Oct. 22, 1974 1 1 SUBSTITUTED BETA-ARYLAMIDOACRYLIC ACIDS [75] Inventors: Robert Thomas Buckler,

Edwardsburg, Mich; Harold Eugene Hartzler, Elkhart, Ind.

Related US. Application Data [62] Division of Ser. No. 81,622. Octv 16. 1970, Pat. No.

[52] US. Cl. 260/465 D, 260/295 AM, 260/295.5 A, 260/471 A, 260/482 R,

[51] Int. Cl. C07c 121/78 [58] Field of Search; 260/465 D [56] References Cited OTHER PUBLICATIONS Barker: .1. Chem. 800., pp. 317-319, (1954).

Primary Examiner-Lewis Gotts Assistant Examiner-Dolph H. Terrence 57 ABSTRACT Certain substituted B-arylamidoacrylic acids and a method of preparing them are disclosed. These com pounds are useful as antiinflammatory and diuretic agents.

2 Claims, No Drawings SUBSTITUTED BETA-ARYLAMIDOACRYLIC ACIDS This is division of application Ser. No. 81,622 filed Oct. 16, 1970, now US. Pat. No. 3,770,821.

SUMMARY OF THE INVENTION Compounds of the present invention correspond to the formula dosage of one millimole per kilogram of body weight,

the antiinflammatory effect is observed as a significant reduction in the effusive response to intrapleural injection of Evans Blue: Carrageenin.

Compounds included within the scope of this invention can be prepared as shown below wherein R, R, and

R are as previously defined and R is methyl or ethyl:

Thus, the esters of formula B are acylated with an R- substituted acid chloride according to the known procedure described in Berichte, 42, 3912 (1910) to yield the ,B-arylamidoacrylate esters of formula C which are carefully saponified with aqueous potassium hydroxide in isopropanol to produce the desired products of formula A as crystalline solids soluble in alkali. Alternatively, the t-butyl esters of formula D can be hydrolyzed by dissolving them in sulfuric acid and pouring the resulting solution over crushed ice to obtain the desired fi-arylamidoacrylic acids. Specific embodiments of both procedures are set forth in the examples which follow.

2 PREFERRED EMBODIMENTS- EXAMPLE 1 R, and R are methyl and R is p-methoxyphenyl in formula A.

A suspension of 35 grams (0.13 mole) of ethyl B-(pmethoxybenzoylamino)-a-methylcrotonate (melting at 97C.) in 150 ml. of 66 percent aqueous isopropanol containing 8.65 grams (0.13 mole) of percent potassium hydroxide was stirred at room temperature for 24 hours. The yellow solution which formed was filtered and diluted with 3 liters of hot water and 40 ml. of acetic acid. The precipitate was collected, dried and recrystallized from methanol to give 19 grams of ,B-(pmethoxybenzoylamino)-a-methy1crotonic acid as a white solid which melted at C. and contained 5.53 percent nitrogen versus the calculated value of 5.62 percent nitrogen.

EXAMPLE 2 R, is methyl, R is hydrogen and R is 3,4- dichlorophenyl in formula A.

A solution of 6.6 grams (0.02 mole) of t-butyl-B- (3,4-dichlorobenzoylamino)crotonate (melting point 102C.) in 50 ml. of 98 percent sulfuric acid was allowed to stand for 3 hours at room temperature and Y then poured over crushed ice. The solid which formed was collected, dried and suspended in one liter of boiling water for 5 minutes, then cooled and filtered. Upon recrystallization from benzene, there was obtained 0.6 gram of B-( 3,4-dichlorobenzoylamino) crotonic acid as a white solid with a melting point of 167C. This compound analyzed 5.20 percent nitrogen compared to 5.1 1 percent nitrogen calculated.

EXAMPLE 3 R, is phenyl, R is hydrogen and Ris phenyl in formula A.

A solution of 27 grams (0.092 mole) of ethyl B-benzamidocinnamate (b.p. 195C. at 0.5 mm. pressure) in 300 ml. of 66'percent aqueous isopropanol containing 6 grams of 85 percent potassium hydroxide was stirred for 24 hours at room temperature. The isopropanol was then removed under vacuum andthe residue diluted with water. The insoluble material which formed was filtered and the filtrate acidified to produce the desired B-benzamidocinnamic acid as a white solid melting at 152C. The yield was 14 grams or 57 percent of theory. Upon analysis, the acid product was found to contain 5.02 percent nitrogen compared to the calculated value of 5.24 percent nitrogen.

EXAMPLES 4 14 By following the saponification procedure described in Example 1, other compounds of formula Awere prepared in-which R, was always methyl, R was always hydrogen and R was as shown in the table below:

EXAMPLE NITROGEN NO. R M.P. C. Cale. Found YlELD 4 4-fluoropheny1 155 6.28 6.18 34 5 3-chlorophenyl 146 5.84 5.72 23 6 4-chlorophenyl 149 5.84 6.06 5 7 4-bromophenyl 164 4.93 4.84 7 8 4-methylpheny1 150 6.39 6.29 37 9 4-ethylphenyl 111 6.00 5.82 11 10 4-isopropylphenyl l 14 5.67 5.77 12 1 1 4-t-butylphenyl 136 5.36 5.21 15 12 4-cyanophenyl 177 12.17 12.21 2 13 4-methoxyphenyl 147 5.95 5.71 13 14 4-dimethylaminophenyl 142 11.28 1 1.32 37 4 EXAMPLES 25 27 By saponifying ethyl B-benzamido-a-ethylcrotonate (melting at 75 C.) as shown in Example 1, the compound of formula A wherein R was methyl, R was EXAMPLE N0. STARTING CROTONATE ESTER M.P. c. 5 ethyl and R was phenyl was readily obtained in 37 per- 4 ethyl fi (4 fluowbenmfido) cent yield as a crystalline solid with a melting point of 5 methyl 3.h|0mb ;nZ-..m;d0,. g7 127C. and a nitrogen content of 5.97 percent com- 9 g'zj'g gg g tg pared to 6.01 percent nitrogen calculated.

e r l' O CnZi/UTH 8 why] B (4 methy|bcnwmido, Similarly, the saponification of ethyl [3-(4- 3 w: g'ggg y nlllnlldokd l0 bromobenzamido) -a-ethylcrotonate (melting point me "150 1'0 C1121! ll I H y, 74 83 C.) with aqueous KOH in isopropanol produced a :2 metlfiy: p- -c unobei i zumidni- 173 percent yield of the compound of formula A in which met y B-( -methoxy enzumido)- lll [4 methyl MMimemyluminobenzumido) H7 R was methyl, R was ethyl and R was 4 brornophenyl. Said compound melted at 150 C. and contained 4.40 (hp at l mm.) percent nitrogen whereas the calculated value was 4.49

percent nitrogen. EXAMPLES 15 24 Likewise, saponification of ethyl oz-ethyl-B-(4- isopropylbenzamido)crotonate produced a 33 percent the Same manner as that des crlbed Example 11 yield of the compound of formula A wherein R, was still other compounds corresponding to formula A were 10 methyl, R2 was ethyl and R was 4 isopropylphenyl prfapared m wh'ch R1 R2 were alwflys methyl 9 which melted at l 127C. and upon analysis was found to R in each example was varied as shown in the following contain 504 percent nitrogen Compared to 509 table: cent nitrogen calculated.

. EXAMPLE ZZ'NiTROGi-iii NO. R M.P. C Cale. Found YIELD l5 phenyl 155 6.39 6.25 47 16 4-chlorophenyl l7l 5.52 5.36 2] l7 3,4-dichlorophenyl 183 4.86 4.86 44 I8 3,-bromophenyl 172 4.70 4.35 37 I9 3.5-dibromophenyl i82 3.72 3.75 22 3-iodophenyl 171 4.06 4.05 52 2i 4-iodophenyl [84 4.06 4.i0 s7 22 4-pyridyl i70 12.72 12.45 19 23 4-isopropylphenyl 141 5.36 5.30 36 24 4-t-burylphenyl I67 5.09 4.96

The starting a-methylcrotonate esters used in the UBll11lllng the llprolirite esters formula C previous examples were as follows: Whefeln 1 f 2 are P PY or butyl, 3 15 methyl or ethyl and R is 2,4,5-trichlorophenyl, 4-n-butylphenyl, 40 4-n-propoxyphenyl or 4-diethylaminophenyl and samg STARTINC M p 0C ponifying said esters as shown in Example 1, the corre- Q.METHYILCROTONATE ESTER sponding acids of formula are obtained in which R,,

R and R represent the radicals designated. l5 ethyl B-bcnzamido- 96 l6 ethyl fl-(4-chlorobenzumido)- [28 what clalmed 17 ethyl /3-(3.4-dichlorobenzamido)- I46 A mp n of the f rm la 18 cthyl B-(3-bromobcnzuniido)- 105 I9 ethyl [H3.5'dibromobenzamido)- 99 A M. WW. 20 cthyl fi-(3-iodobenzamido)- I05 21 ethyl fl-(4-iodobenzamido)- 128 CONH C=$*CO2H C d ON {ti 2 ontinue V. 7....

EXAMPLE NO. STARTING M.P.. C. P

a-METHYLCROTONATE ESTER R 15 methyl; and

2 22 ethyl B-isonicotinoyl- I39 R 18 hydrogen 23 ethyl B44-isopropylbcnzaimido)- 61 2. A compound as in claim 1: B-(4-cyanoben- 24 ethyl B-(4-t-hutylbenztiniido)- 92 zamido) crotonic acid 

1. A COMPOUND OF THE FORMULA
 2. A compound as in claim 1: Beta -(4-cyanobenzamido)-crotonic acid. 